Different lines of evidence support the notion that psychiatric disorders result from the interaction of vulnerability genes and environmental factors. The incomplete penetrance (discordance) of psychiatric disorders in identical twins has been hypothesized to be the result of environmental influences. Likewise, genetic differences have been postulated to be responsible for the seeming resilience or vulnerability to psychiatric symptoms seen in subjects exposed to similar environmental situations. Although this gene- environment diathesis of psychiatric disorders has intuitive appeal, neither the genes conferring susceptibility nor the environmental factors that increase the risk of psychiatric morbidity are well understood. Recently some progress has been made in identifying both susceptibility genes and environmental factors that may influence the outcome in major depression, the most common psychiatric disorder that takes an enormous toll on individuals, their families, and society. A highly influential study by Caspi demonstrated that certain promoter variants of the serotonin transporter gene (5HTT) interact with either early life stress (childhood maltreatment) or adult stresses (job loss, divorce, etc.) to modulate the likelihood of depressive symptoms, diagnosed major depression, and suicidal behavior in the study subjects. Specifically, the study found that promoter variants that reduce transcriptional efficiency of the 5HTT increase depression-related phenotypes whereas variants that have higher expression confer resilience to childhood or adult stresses. The availability of a mouse model of a 5HTT-environment interaction allows us to ask several specific questions regarding the positive and negative ways that the environment may be manipulated to reduce or increase the expression of depression-related behaviors. In addition, a mouse model offers the possibility to investigate the neural substrates that mediate the environmental impact on behavior. This line of investigation offers the possibility of gaining new understanding regarding the pathogenesis of depressive disorders.